Maintenance of genome stability is a prerequisite for the development of the nervous system. The rapid rate of DNA replication and cell proliferation during neurogenesis highlights the need for multiple, efficient pathways that safeguard genome integrity. DNA repair mechanisms are also crucial in post-mitotic neurons as they stimulate synaptic changes that influence learning and memory and prevent neurodegeneration. Our two objectives are to determine the essential, novel roles of the Structural Maintenance of Chromosomes (SMC) complex, SMC5/6, during neurodevelopment (Aim 1) and post-mitotic neuronal activity (Aim 2). Hypomorphic mutations of an SMC5/6 component cause microcephaly and primordial dwarfism. We hypothesize that the SMC5/6 complex maintains genome integrity in proliferating neural stem cells. For aim 1, we have developed a conditional knockout (cKO) allele of mouse Smc5 that we use to destabilize the SMC5/6 complex during neurodevelopment. Smc5 cKO mice develop microcephaly, and we have demonstrated that this is caused by activation of the DNA damage response pathway (ATM-CHK2-p53). We have already harvested most samples needed to complete this aim, and with reference to the R03 scope descriptions: Aim 1 is a ?small, self-contained research project?. Upon neuron activation, Topoisomerase II? rapidly forms DNA double-strand breaks at the promoters of early response transcription factors, relieving the topological barriers that were inhibiting RNA Polymerase II from initiating transcription. These transcription factors coordinate many cellular, circuitry and cognitive functions, including neurite outgrowth, synapse development and maturation, balance between excitatory and inhibitory synapses, and learning and memory. Research using yeast and mammalian cell culture have shown that SMC5/6 and Topoisomerase II physically and functionally interact. Furthermore, we have confirmed that Topoisomerase II? and SMC5/6 are co-expressed and interact in post-mitotic cortical neurons. Therefore, we hypothesize that the SMC5/6 complex is required for normal expression of early response genes in post-mitotic neurons. We have shown that we can rapidly and reversibly deplete the SMC5/6 complex using an auxin-inducible degron system. In Aim 2, we will use this system to determine whether SMC5/6 is important the transcription of early and late neuronal response genes. Aim 2 fits within the description of a ?pilot study? that could result in very novel findings that produce data for further funding opportunities. Our proposal will make significant contributions to understanding of the etiology of neurodevelopmental disorders and neurodegeneration. Furthermore, we will determine whether the physical and functional overlap between Topoisomerase II? and SMC5/6 spans to include the control of post-mitotic neural function.